TMPRSS4

Summary

TMPRSS4 (transmembrane serine protease 4, HGNC:11878) is a protein-coding gene on chromosome 11q23.3, encoding Transmembrane protease serine 4 (Q9NRS4). Plasma membrane-anchored serine protease that directly induces processing of pro-uPA/PLAU into the active form through proteolytic activity.

This gene encodes a member of the serine protease family. Serine proteases are known to be involved in a variety of biological processes, whose malfunction often leads to human diseases and disorders. This gene was identified as a gene overexpressed in pancreatic carcinoma. The encoded protein is membrane bound with a N-terminal anchor sequence and a glycosylated extracellular region containing the serine protease domain. The protein has been found to promote SARS-CoV-2 entry into host cells.

Source: NCBI Gene 56649 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cardiomyopathy, dilated, 2I (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 176 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 4
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_019894

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11878
Approved symbol	TMPRSS4
Name	transmembrane serine protease 4
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	TMPRSS3, MT-SP2, CAP2
Ensembl gene	ENSG00000137648
Ensembl biotype	protein_coding
OMIM	606565
Entrez	56649

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 14 protein_coding, 7 retained_intron, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000437212, ENST00000517483, ENST00000517544, ENST00000518413, ENST00000518610, ENST00000519126, ENST00000519236, ENST00000519813, ENST00000520063, ENST00000522151, ENST00000522307, ENST00000522462, ENST00000522824, ENST00000523251, ENST00000523770, ENST00000524218, ENST00000528118, ENST00000534111, ENST00000616579, ENST00000714375, ENST00000714378, ENST00000896311, ENST00000896312, ENST00000896313, ENST00000896314, ENST00000951076

RefSeq mRNA: 6 — MANE Select: NM_019894 NM_001083947, NM_001173551, NM_001173552, NM_001290094, NM_001290096, NM_019894

CCDS: CCDS31684, CCDS44743, CCDS53716, CCDS53717, CCDS76482

Canonical transcript exons

ENST00000437212 — 13 exons

Exon	Start	End
ENSE00001292654	118094816	118094855
ENSE00002096545	118077078	118077305
ENSE00002121417	118098985	118099098
ENSE00002182667	118117902	118121890
ENSE00003509163	118115138	118115280
ENSE00003512276	118111741	118111900
ENSE00003539015	118103101	118103253
ENSE00003585962	118107774	118107875
ENSE00003618968	118104691	118104820
ENSE00003647038	118108856	118108896
ENSE00003652413	118117305	118117454
ENSE00003654765	118113269	118113435
ENSE00003666776	118114829	118114927

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 98.96.

FANTOM5 (CAGE): breadth broad, TPM avg 5.1991 / max 483.2150, expressed in 297 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
116965	4.9760	294
116964	0.2231	80

Top tissues by expression

279 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	98.96	gold quality
lower esophagus mucosa	UBERON:0035834	98.93	gold quality
nasal cavity epithelium	UBERON:0005384	98.57	gold quality
palpebral conjunctiva	UBERON:0001812	97.84	gold quality
esophagus mucosa	UBERON:0002469	97.48	gold quality
rectum	UBERON:0001052	97.31	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.54	gold quality
epithelium of nasopharynx	UBERON:0001951	94.86	gold quality
colonic mucosa	UBERON:0000317	94.71	gold quality
esophagus squamous epithelium	UBERON:0006920	94.53	gold quality
gall bladder	UBERON:0002110	94.40	gold quality
epithelium of esophagus	UBERON:0001976	94.27	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.67	gold quality
nasal cavity mucosa	UBERON:0001826	93.49	gold quality
ileal mucosa	UBERON:0000331	91.95	gold quality
colonic epithelium	UBERON:0000397	91.31	gold quality
duodenum	UBERON:0002114	90.83	gold quality
pharyngeal mucosa	UBERON:0000355	90.74	gold quality
squamous epithelium	UBERON:0006914	90.57	gold quality
oral cavity	UBERON:0000167	90.10	gold quality
epithelium of bronchus	UBERON:0002031	89.06	gold quality
pancreatic ductal cell	CL:0002079	88.94	gold quality
transverse colon	UBERON:0001157	88.85	gold quality
mucosa of urinary bladder	UBERON:0001259	88.84	gold quality
bronchus	UBERON:0002185	88.76	gold quality
bronchial epithelial cell	CL:0002328	87.36	gold quality
urinary bladder	UBERON:0001255	87.04	gold quality
gingiva	UBERON:0001828	86.52	gold quality
gingival epithelium	UBERON:0001949	86.51	gold quality
metanephros cortex	UBERON:0010533	86.30	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	61.62
E-MTAB-6386	no	18.05
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

71 targeting TMPRSS4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-122B-5P	99.46	70.81	1457
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-4796-5P	99.34	70.06	810
HSA-MIR-664A-3P	99.22	71.08	2696

Literature-anchored findings (GeneRIF, showing 40)

• TMPRSS4 plays a role in invasion, metastasis, migration and adhesion in cancer cells. TMPRSS4 may contribute to tumor cell invasion and metastasis by promoting an epithelial-mesenchymal transition(EMT) through the strong SIP1/ZEB2 induction. (PMID:17968309)
• The authors provide evidence that TMPRSS2 and TMPRSS4 activate the 1918 HA by cleavage and therefore may promote viral spread in lung tissue. (PMID:19158246)
• TMPRSS4 expression was significantly higher in human colorectal cancer tissues from advanced stages than in that of early stage. (PMID:20118200)
• RNAi-mediated knockdown of TMPRSS2 and TMPRSS4 in Caco-2 cells, which released fully infectious virus without trypsin treatment, markedly reduced the spread of influenza virus, demonstrating that these proteases were responsible for activation of HA. (PMID:20631123)
• Overexpression of TMPRSS4 has a critical role in radiation-induced long-term dissemination and metastasis of residual HCC by facilitating EMT. (PMID:21637307)
• Kaplan-Meier curves demonstrated that high levels of TMPRSS4 were significantly associated (P=0.017) with reduced overall survival in the patients with SCC histology, whereas no correlation was found for the AC histology (PMID:22067904)
• results demonstrate overexpression of TMPRSS4 in non-small cell lung carcinoma at both the mRNA and protein levels. In addition, our findings suggest that expression of TMPRSS4 in the tumor microenvironment is regulated by hypoxia. (PMID:22692880)
• Progression and metastatic potential of several cancers is concordant with an increased expression of TMPRSS4. (PMID:22944691)
• TMPRSS4 expression is a putative biological marker for breast cancer and is an indicator of poor prognosis. (PMID:23420063)
• Expression of TMPRSS4 in gastric cancer is significantly associated with lymph node and distant metastasis, high Erk1 expression, and poor prognosis. (PMID:23922976)
• A mutation in the serine protease TMPRSS4 in a novel pediatric neurodegenerative disorder (PMID:23957953)
• TMPRSS4 induced the transcription of uPA gene through activating the transcription factors Sp1, Sp3, and AP-1 in a JNK-dependent manner and that the induction of uPA was required for TMPRSS4-mediated cancer cell invasion. (PMID:23978400)
• High TMPRSS4 expression is associated with cervical squamous cell carcinoma. (PMID:24012692)
• High expression of TMPRSS4 was significantly associated with advanced TNM stage. (PMID:24072509)
• TMPRSS4 was an independent predictor of OS and DFS. (PMID:24132607)
• Our data suggest that TMPRSS4 positivity is associated with GC invasion and lymph node metastasis. We propose TMPRSS4 expression as an indicator of poor prognosis in GC patients (PMID:24299317)
• TMPRSS4 was associated with CRC stage and regulated the proliferation and self-renewal ability of colon cancer cells; TMRPSS4 was involved in the development and progression of CRC. (PMID:24335200)
• TMPRSS4 directly converted inactive pro-uPA into the active form through its proteolytic activity. Conditioned medium from cells overexpressing TMPRSS4 showed that the active TMPRSS4 protease domain is released and is associated with the plasma membrane. (PMID:24434139)
• We have demonstrated for the first time a new molecular pathway that connects TMPRSS4 and integrin alpha5 through miR-205 to regulate cancer cell invasion and metastasis (PMID:24434435)
• increased TMPRSS4 expression was an independent predictor of poor prognosis for overall survival in gallbladder cancer. patients. (PMID:24532432)
• On the basis of this information and the structural characteristics of this druggable protease, we suggest that TMPRSS4 could be a novel potential therapeutic target in solid tumours. (PMID:25203520)
• TMPRSS4 is overexpressed in thyroid cancer and TMPRSS4-CREB signaling is needed to sustain thyroid cancer cell proliferation. (PMID:25244400)
• TMPRSS4 is upregulated by silencing of TFPI-2 through aberrant DNA methylation and contributes to oncogenesis in non-small cell lung cancer. (PMID:25414083)
• In prostate cancer, high TMPRSS4 expression was significantly associated with advanced tumor stage and lymphatic metastasis. (PMID:25550850)
• The increase of TMPRSS4 expression may be a key event for HCC progression and may be regarded as a potential prognostic marker for HCC. (PMID:26190376)
• suggesting that TMPRSS4 is associated with a cancer stem cells phenotype in patients’ tumors (PMID:26546046)
• TMPRSS4 expression is associated with postoperative recurrence. In addition, the current survival curves demonstrated that TMPRSS4 expression is associated with statistically significant differences in survival among patients with lung adenocarcinoma. (PMID:26722035)
• TMPRSS4 is a novel independent prognostic biomarker regulated by epigenetic changes in lung squamous cell carcinomas (PMID:26989022)
• High TMPRSS4 expression is associated with pancreatic adenocarcinoma. (PMID:26993610)
• We conclude that TMPRSS4 overexpression in solid tumors is associated with patients’ poor prognosis. TMPRSS4 could be a valuable prognosis biomarker or a promising therapeutic target of solid tumor. (PMID:27344186)
• TMPRSS4 modulates both invasion and proliferation via Slug and cyclin D1, which is a previously unrecognized pathway that may regulate metastasis and cancer progression (PMID:27385093)
• TMPRSS4 overexpression promoted the proliferation, invasion and migration of breast cancer cells by possibly inducing epithelial-mesenchymal transition (PMID:28259959)
• we demonstrated a mechanistic cascade of TMPRSS4 up-regulating STAT3 activation and subsequent TWIST1 expression, leading to prostate cancer migration. (PMID:28466252)
• These results revealed that CLDN1 contributed to cancer stem cell features of hepatocellular carcinoma, which was altered by TMPRSS4 expression via ERK1/2 signaling pathway, providing promising targets for novel specific therapies. (PMID:28651932)
• TMPRSS4 protein expression in esophageal carcinoma was correlated with patient demographic characteristics, tumor type, high TNM stages and overall survival. (PMID:29254316)
• Data suggest that miR-551b-3p functions as a tumour suppressor gene in gastric cancer, and its function is regulated by long noncoding RNAs (lncRNAs) SMARCC2/miR-551b-3p/transmembrane protease, serine 4 protein (TMPRSS4) axis. (PMID:29337109)
• TMPRSS4 is overexpressed in Idiopathic pulmonary fibrosis lungs. (PMID:29529050)
• The miR125a5p/TMPRSS4/NFkappaB axis may thus provide novel insight into the pathogenic mechanisms of lung adenocarcinoma and may be used in the development of novel treatment strategies for lung adenocarcinoma . (PMID:29750426)
• The authors demonstrated that TMPRSS4 expression was significantly upregulated in fine needle aspiration biopsy specimens from Papillary thyroid cancer patients compared with benign nodules, and appeared to be a helpful diagnostic marker for distinguishing malignant from benign nodules. (PMID:30518486)
• TMPRSS4 silencing in breast cancer reduces cells proliferation by promoting cell cycle arrest (PMID:31244309)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tmprss4	ENSMUSG00000032091
rattus_norvegicus	Tmprss4	ENSRNOG00000026650
drosophila_melanogaster	CG9673	FBGN0030775
drosophila_melanogaster	CG4477	FBGN0035971
drosophila_melanogaster	CG17404	FBGN0038001
drosophila_melanogaster	CG12256	FBGN0038002
drosophila_melanogaster	CG3916	FBGN0038003
drosophila_melanogaster	CG17477	FBGN0038479
drosophila_melanogaster	CG4053	FBGN0038482
drosophila_melanogaster	CG31269	FBGN0051269
drosophila_melanogaster	CG32808	FBGN0052808
drosophila_melanogaster	Phae2	FBGN0263235
drosophila_melanogaster	Send2	FBGN0264253

Paralogs (12): PRSS54 (ENSG00000103023), KLK14 (ENSG00000129437), KLK8 (ENSG00000129455), KLK3 (ENSG00000142515), KLK1 (ENSG00000167748), KLK4 (ENSG00000167749), KLK2 (ENSG00000167751), KLK5 (ENSG00000167754), KLK11 (ENSG00000167757), KLK7 (ENSG00000169035), KLK12 (ENSG00000186474), PRSS58 (ENSG00000258223)

Protein

Protein identifiers

Transmembrane protease serine 4 — Q9NRS4 (reviewed: Q9NRS4)

Alternative names: Channel-activating protease 2, Membrane-type serine protease 2

All UniProt accessions (10): Q9NRS4, A0A087WTU6, A0AAQ5BHV3, A0AAQ5BHV4, E5RIH1, E5RJR8, E7ESG9, G3V124, H0YAX8, H0YBM5

UniProt curated annotations — full annotation on UniProt →

Function. Plasma membrane-anchored serine protease that directly induces processing of pro-uPA/PLAU into the active form through proteolytic activity. Seems to be capable of activating ENaC. (Microbial infection) In gut epithelial cells, facilitates human coronavirus SARS-CoV-2 infection through, at least, the cleavage of coronavirus spike glycoproteins which activates the glycoprotein for host cell entry.

Subcellular location. Cell membrane Secreted.

Tissue specificity. High levels in pancreatic, gastric, colorectal and ampullary cancer. Very weak expression in normal gastrointestinal and urogenital tract. Coexpressed with ACE2 within mature enterocytes.

Post-translational modifications. Proteolytically processed; probably by an autocatalytic mechanism.

Similarity. Belongs to the peptidase S1 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NRS4-1	1	yes
Q9NRS4-2	2
Q9NRS4-3	3
Q9NRS4-4	4

RefSeq proteins (6): NP_001077416, NP_001167022, NP_001167023, NP_001277023, NP_001277025, NP_063947* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001190	SRCR	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR036772	SRCR-like_dom_sf	Homologous_superfamily
IPR043504

Pfam: PF00089, PF15494

UniProt features (31 total): disulfide bond 8, active site 3, splice variant 3, sequence variant 3, domain 3, chain 2, glycosylation site 2, topological domain 2, mutagenesis site 2, site 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRS4-F1	88.01	0.67

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (4): 387 (charge relay system); 204–205 (cleavage); 245 (charge relay system); 290 (charge relay system)

Disulfide bonds (8): 64–83, 77–92, 127–183, 140–193, 196–310, 230–246, 356–372, 383–410

Glycosylation sites (2): 130, 178

Mutagenesis-validated functional residues (2):

Position	Phenotype
290	abolishes protease activity.
387	abolishes protease activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 449 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, MODULE_52, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOCC_SECRETORY_GRANULE, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GOZGIT_ESR1_TARGETS_DN, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_LYASE_ACTIVITY, FRASOR_RESPONSE_TO_SERM_OR_FULVESTRANT_DN, PATIL_LIVER_CANCER, SENESE_HDAC1_AND_HDAC2_TARGETS_DN

GO Biological Process (6): proteolysis (GO:0006508), response to wounding (GO:0009611), regulation of gene expression (GO:0010468), protein processing (GO:0016485), negative regulation of growth rate (GO:0045967), positive regulation of viral entry into host cell (GO:0046598)

GO Molecular Function (5): serine-type endopeptidase activity (GO:0004252), serine-type peptidase activity (GO:0008236), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (7): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), membrane (GO:0016020), secretory granule (GO:0030141), extracellular region (GO:0005576), cytoplasm (GO:0005737), endomembrane system (GO:0012505)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein metabolic process	1
response to stress	1
gene expression	1
regulation of macromolecule biosynthetic process	1
proteolysis	1
protein maturation	1
regulation of growth rate	1
negative regulation of growth	1
regulation of viral entry into host cell	1
symbiont entry into host cell	1
positive regulation by symbiont of entry into host	1
positive regulation of viral life cycle	1
endopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
membrane	1
cell periphery	1
endomembrane system	1
secretory vesicle	1
intracellular anatomical structure	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

1264 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMPRSS4	PJVK	Q0ZLH3	738
TMPRSS4	ACE2	Q9BYF1	706
TMPRSS4	MYO15A	Q9UKN7	697
TMPRSS4	FURIN	P09958	681
TMPRSS4	MYO6	Q9UM54	670
TMPRSS4	TMC1	Q8TDI8	669
TMPRSS4	SLC26A4	O43511	657
TMPRSS4	GJB2	P29033	646
TMPRSS4	ZFYVE9	O95405	632
TMPRSS4	OTOF	Q9HC10	629
TMPRSS4	CDH23	Q9H251	620
TMPRSS4	LOXHD1	Q8IVV2	611
TMPRSS4	CTSL	P07711	600
TMPRSS4	OTOA	Q7RTW8	590
TMPRSS4	MYO7A	P78427	582
TMPRSS4	STRC	Q7RTU9	582

IntAct

37 interactions, top by confidence:

A	B	Type	Score
TMPRSS4	KASH5	psi-mi:“MI:0915”(physical association)	0.560
TMEM79	TMPRSS4	psi-mi:“MI:0915”(physical association)	0.560
KASH5	TMPRSS4	psi-mi:“MI:0915”(physical association)	0.560
BNIP3L	TMPRSS4	psi-mi:“MI:0915”(physical association)	0.560
SIGLEC12	TMPRSS4	psi-mi:“MI:0915”(physical association)	0.560
FNDC9	TMPRSS4	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	TMPRSS4	psi-mi:“MI:0915”(physical association)	0.560
GPX8	TMPRSS4	psi-mi:“MI:0915”(physical association)	0.560
ERVFRD-1	TMPRSS4	psi-mi:“MI:0915”(physical association)	0.560
SUSD3	TMPRSS4	psi-mi:“MI:0915”(physical association)	0.560
RASGRP4	TMPRSS4	psi-mi:“MI:0915”(physical association)	0.560
FAM209A	TMPRSS4	psi-mi:“MI:0915”(physical association)	0.560
TMPRSS4	CSNK1D	psi-mi:“MI:0915”(physical association)	0.560
TMPRSS4	BNIP3L	psi-mi:“MI:0915”(physical association)	0.000
TMPRSS4	SIGLEC12	psi-mi:“MI:0915”(physical association)	0.000
TMPRSS4	GPX8	psi-mi:“MI:0915”(physical association)	0.000
TMPRSS4	ERVFRD-1	psi-mi:“MI:0915”(physical association)	0.000
TMPRSS4	SUSD3	psi-mi:“MI:0915”(physical association)	0.000
TMPRSS4	RASGRP4	psi-mi:“MI:0915”(physical association)	0.000
TMPRSS4	FAM209A	psi-mi:“MI:0915”(physical association)	0.000
TMPRSS4	FNDC9	psi-mi:“MI:0915”(physical association)	0.000
TMPRSS4	CLRN1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (370): CLEC7A (Two-hybrid), TMEM79 (Two-hybrid), CCDC155 (Two-hybrid), SYNE4 (Two-hybrid), TMPRSS4 (Two-hybrid), TMPRSS4 (Two-hybrid), TMPRSS4 (Two-hybrid), SUSD3 (Two-hybrid), CLRN1 (Two-hybrid), GPX8 (Two-hybrid), RASGRP4 (Two-hybrid), FNDC9 (Two-hybrid), ERVFRD-1 (Two-hybrid), SIGLEC12 (Two-hybrid), KIAA1467 (Affinity Capture-MS)

ESM2 similar proteins: A6H6T1, A6MFK7, A6MFK8, O15393, O19045, O70169, P00741, P00742, P00749, P04185, P15638, P16227, P18292, P19221, P31394, P33587, P49150, P57727, P70375, P98119, P98121, Q05589, Q14520, Q1L658, Q1L659, Q3UQ41, Q4QXT9, Q56VR3, Q58L93, Q58L94, Q58L95, Q58L96, Q5E9Z2, Q5R537, Q5RF29, Q5U405, Q6AXZ6, Q6AY28, Q6DIV5, Q6L711

Diamond homologs: A0A126GUP6, A0A182C2Z2, A0A1S4H5M5, A8JUP7, B5U2W0, B7YZU2, F5HKX0, O15393, O35453, O60235, O60259, O97366, P00774, P03951, P03952, P05049, P05981, P08419, P09871, P10323, P13582, P14272, P21902, P23578, P25155, P26262, P28175, P29293, P31394, P33587, P35035, P35036, P35037, P35039, P35041, P35045, P35046, P35047, P40313, P48038

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
TMPRSS4	“up-regulates activity”	S	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

176 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	129
Likely benign	12
Benign	1

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
2574649	NM_006366.3(CAP2):c.636+1G>A	Pathogenic
2574650	NM_006366.3(CAP2):c.948T>G (p.Tyr316Ter)	Pathogenic
2574651	NM_006366.3(CAP2):c.1288del (p.Cys430fs)	Pathogenic
4845338	NM_006366.3(CAP2):c.870del (p.Ser291fs)	Likely pathogenic

SpliceAI

4828 predictions. Top by Δscore:

Variant	Effect	Δscore
11:118091957:T:G	donor_gain	1.0000
11:118099099:G:GG	donor_gain	1.0000
11:118103088:A:AG	acceptor_gain	1.0000
11:118103089:C:G	acceptor_gain	1.0000
11:118103099:A:AG	acceptor_gain	1.0000
11:118103100:G:GA	acceptor_gain	1.0000
11:118103249:GGCAG:G	donor_gain	1.0000
11:118103250:GCAG:G	donor_gain	1.0000
11:118103250:GCAGG:G	donor_gain	1.0000
11:118103253:GGTG:G	donor_loss	1.0000
11:118103254:G:A	donor_loss	1.0000
11:118103255:T:G	donor_loss	1.0000
11:118104686:CCCA:C	acceptor_loss	1.0000
11:118104687:CCA:C	acceptor_loss	1.0000
11:118104688:CA:C	acceptor_loss	1.0000
11:118104689:A:AG	acceptor_gain	1.0000
11:118104689:AGTCC:A	acceptor_gain	1.0000
11:118104690:G:GA	acceptor_gain	1.0000
11:118104690:GT:G	acceptor_gain	1.0000
11:118104690:GTC:G	acceptor_gain	1.0000
11:118104690:GTCC:G	acceptor_gain	1.0000
11:118104690:GTCCG:G	acceptor_gain	1.0000
11:118104795:GCCT:G	donor_gain	1.0000
11:118104818:CAG:C	donor_loss	1.0000
11:118104820:GGT:G	donor_loss	1.0000
11:118104821:GTAA:G	donor_loss	1.0000
11:118104822:T:A	donor_loss	1.0000
11:118107762:T:A	acceptor_gain	1.0000
11:118111897:TCAGG:T	donor_loss	1.0000
11:118111899:AGG:A	donor_loss	1.0000

AlphaMissense

2884 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:118113399:G:C	A292P	0.989
11:118113400:C:A	A292D	0.989
11:118113403:T:C	L293P	0.985
11:118103172:T:A	C77S	0.983
11:118103173:G:C	C77S	0.983
11:118103190:T:A	C83S	0.977
11:118103191:G:C	C83S	0.977
11:118117436:G:C	W428C	0.976
11:118117436:G:T	W428C	0.976
11:118111809:T:A	W218R	0.969
11:118111809:T:C	W218R	0.969
11:118111854:A:C	S233R	0.965
11:118111856:C:A	S233R	0.965
11:118111856:C:G	S233R	0.965
11:118103190:T:C	C83R	0.963
11:118111811:G:C	W218C	0.963
11:118111811:G:T	W218C	0.963
11:118117434:T:A	W428R	0.963
11:118117434:T:C	W428R	0.963
11:118103133:T:A	C64S	0.956
11:118103134:G:C	C64S	0.956
11:118103173:G:A	C77Y	0.954
11:118117365:A:C	S405R	0.954
11:118117367:T:A	S405R	0.954
11:118117367:T:G	S405R	0.954
11:118115194:T:A	C356S	0.953
11:118115195:G:C	C356S	0.953
11:118111818:A:C	S221R	0.952
11:118111820:C:A	S221R	0.952
11:118111820:C:G	S221R	0.952

dbSNP variants (sampled 300 via entrez): RS1000026219 (11:118090913 C>T), RS1000035514 (11:118108374 C>T), RS1000121025 (11:118075841 G>C), RS1000133899 (11:118094083 A>C), RS1000144979 (11:118114277 T>C), RS1000193387 (11:118116054 C>T), RS1000291455 (11:118110477 G>C), RS1000389494 (11:118104328 T>C), RS1000400891 (11:118096715 G>A), RS1000492269 (11:118112623 C>G,T), RS1000531986 (11:118114788 G>A,C,T), RS1000592909 (11:118108776 A>T), RS1000603297 (11:118077927 C>T), RS1000800460 (11:118097320 A>C,G), RS1000864926 (11:118081658 T>G)

Disease associations

OMIM: gene MIM:606565 | disease phenotypes: MIM:620462

GenCC curated gene-disease

Disease	Classification	Inheritance
cardiomyopathy, dilated, 2I	Moderate	Autosomal recessive
autosomal recessive cerebral atrophy	Supportive	Autosomal recessive
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant

Mondo (3): cardiomyopathy, dilated, 2I (MONDO:0957545), autosomal recessive cerebral atrophy (MONDO:0018218), (MONDO:0015470)

Orphanet (0):

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0003577	Congenital onset
HP:0011463	Childhood onset

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000175_15	Height	7.000000e-07
GCST002616_3	Mitochondrial DNA levels	2.000000e-06
GCST002868_6	Response to serotonin reuptake inhibitors in major depressive disorder	2.000000e-06
GCST005171_43	QT interval	3.000000e-07
GCST90014033_45	Haemorrhoidal disease	2.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006312	mitochondrial DNA measurement
EFO:0005658	response to selective serotonin reuptake inhibitor
EFO:0004682	QT interval

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2331048 (SINGLE PROTEIN), CHEMBL4742321 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 469 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL536151	IMD-0354	1	469

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs910039	CAP2		0.00	0

ChEMBL bioactivities

2 potent at pChembl≥5 of 29 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.22	IC50	6000	nM	CHEMBL2338685
5.00	IC50	1e+04	nM	CHEMBL2313097

PubChem BioAssay actives

2 with measured affinity, of 47 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[4-bromo-3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide	730377: Inhibition of N-terminal His6-tagged recombinant TMPRSS4 (unknown origin) fused with enterokinase cleavage sequence DYKDDDGDYKDDDDK expressed in Escherichia coli BL21 (DE3) using Z-Phe-Arg-7-amido-4-methylcoumarin hydrochloride as substrate by fluorometric analysis	ic50	6.0000	uM
5-chloro-2-hydroxy-N-[4-methyl-3,5-bis(trifluoromethyl)phenyl]benzamide	730377: Inhibition of N-terminal His6-tagged recombinant TMPRSS4 (unknown origin) fused with enterokinase cleavage sequence DYKDDDGDYKDDDDK expressed in Escherichia coli BL21 (DE3) using Z-Phe-Arg-7-amido-4-methylcoumarin hydrochloride as substrate by fluorometric analysis	ic50	10.0000	uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases expression, decreases expression, affects cotreatment	3
Particulate Matter	increases expression, increases abundance	2
beta-lapachone	increases expression	1
butyraldehyde	increases expression	1
fipronil	increases expression	1
CGP 52608	affects binding, increases reaction	1
rofecoxib	increases expression	1
pinostrobin	increases phosphorylation	1
prothioconazole	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Ethinyl Estradiol	affects expression	1
Ibuprofen	affects expression	1
Nickel	increases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases expression	1
Okadaic Acid	increases expression	1
Genistein	affects expression	1

ChEMBL screening assays

21 unique, capped per target: 21 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2343322	Binding	Inhibition of TMPRSS4 in human SW480 cells assessed as inhibition of cell invasion at 0.1 uM relative to control	Discovery of novel 2-hydroxydiarylamide derivatives as TMPRSS4 inhibitors. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.